Update

Dr Kieran Hand ClConsultant Pharmaci st ‐ AiAnti‐IfInfecti ves University Hospital Southampton NHS Foundation Trust

38th UK Medicines Information Practice Development Seminar University of Warwick, 13th – 14th September 2012 A game of two halves

•First half •Second half –An interesting anecdote – Ask the audience Prize-winning schoolgirls take quantum leap from babies’ bottoms to dairy cows’ udders By Jimmy Woulfe, Mid-West Correspondent Thursday, May 03, 2012 Two Co Limerick schoolggyirls have found a widely-used cream for soothing babies’ bottoms is a great remedy for dairy cows with sore udders caused by mastitis. Both girls did their research on the family farms run by their dads. They found th at a t ub of S ud ocrem costi ng €4 can c lear mas titis in a da iry cow just as quickly as widely-used veterinary injections which cost €60 per treatment. Evaluating appropriateness: what factors influence choice / dose / route / duration of therapy?

• Presenting complaint / signs & • Previous antibiotics symptoms • Biochemistry / haematology results / • Evidence of infection (+SIRS) urine dipstick • Past medical history (e.g. prosthetic • Allergy / intolerance valve, epilepsy) •Pregnancy / breastfeeding • Immune status/immunosuppressants •Organ dysfunction • Family / social contacts •GI absorption / swallowing • Occupation / hobbies •Expert advice •Travel history •Source control •Pets / animal contact •Local pathogen epidemiology and • DIAGNOSIS and likely pathogens resistance • Severity of infection • spectrum • Prescriber’s training / experience • Site of infection (penetration) • Peer addivice / consultan t preference • DiDosing regimen (PK/PD) •Local guidelines / policy • Interacting drugs (e.g. iron and • Recent contact with healthcare ) • Recent or previous microbiology / • Ethnicity (e.g . G6PD deficiency). serology investigations. Skin & soft tissue infections: in vitro sensitivities from Southampton GPs 11/12 100 90 80 Penicillin 70 e Flucloxacillin iv

tt 60 50 Doxycycline sensi 40

%% Rifampicin 30 20 Ciprofloxacin 10 0 Staph aureus

Southampton GP isolates 2011/12 Take a chance on me

•Trust me I’m a doctor •I have a remarkable memory for facts • IIm’m going to start you on ‘Cefanmet’ • My rabbit’ s foot has never failed me Ebbinghaus’ forgetting curve (try to remember it) Which of these two men would you send to the supermarket? There is another way…

•Bear with me while I consult our treatment guidelines • Hmm, they don’t seem to cover your particular circumstances •I think I will get some expert advice Hospital pharmacist knowledge of antibiot ics and ifinfect ion

Assessment results by subject area (ITT)

100

75

Baseline (all) % 50 Final (all)

25

0 t iology tibiotic ination ectrum ogen atmen f action f -effects actions nitoring inf man inf nn mm rr pp hh ee oo mm Eli Pat Inte Side epide Antibiotic s Antibiotic Choice of a of Choice Empirical tr Principles of Principles of Mechanis m Diagnosis/mo

Hand K & Jubraj J 2005 (MSc) What do patients deserve?

•Option one: Parachute •Option two: Provide an in a micro/ID doctor IT system for decision‐ (and pharmacist) support 24/7 From maps to Apps

2008 2011 Guiding treatment choice Protecting patients from harm Tailoring treatment to patients

•“Existing guidance on the management of some infections may be too long and complex for many doctors to have time to absorb, according to the Healthcare‐Associated Infections (HCAI) Working Group at the RCP. The group have now produced a handy one‐page summary of guidelines to help busy doctors identify what is most important for them in their routine clinical practice.” De‐skilling? This page intentionally blank Audience empowerment

•Option A •Option B • Revision of the basics – • Heads‐up on the latest choosing an antibiotic trends in resistance / regimen that may save prescribing and a patient’s life (or advances in science of intervening if a regimen infection management is likely to fail) Four main groups of

1. Gram positive 2. GtiGram negative 3. Anaerobes 4. Atypical

Even Ebbinghaus could remember this!

Groups are defined by their response to antibiotics Generally speaking... Gram -ve GI-tract Anaerobes Respiratory Mouth, teeth, Peritonitis throat, sinuses Biliary infection & lower bowel Pancreatitis Abscesses UTI Dental infection PID Peritonitis Pneumonia Appendicitis

Gram +ve Atypicals Skin & Chest Chest and Pneumonia genito-urinary Sinusitis Pneumonia Cellulitis Urethritis Wound infection PID Line infection (Osteomyelitis) Antibiotic spectrum

Legionella, Streptococcus Anaerobic Chlamydi a & Bacteroides Pseudomonas pneumoniae & Streptococci Mycoplasma fragilis aeruginosa Group A, B, C, G &Clostridia pneumoniae

Gram positive Gram negative Atypicals MRSA Staphylococci Streptococci EF Anaerobes Coliforms Resp Pyo ESBL

Antibiotic

Enterococcus Respiratory Extended- MRSA and Gut faecalis & Gram -ve e.g. spectrum beta- Coagulase- bacteria Enterococcus Haemophilus lactamase negative Staph. e.g. EliE. coli faecium influenzae & producers & other Moraxella resistant Gram catarrhalis negatives

Green = Generally Sensitive; Orange = Unreliable; Red = Generally Resistant 1. Narrow-spectrum Gram-positive agents (Staphs and Streps) • Penicillin V/G*, Flucloxacillin • Erythromycin • • Fusidic acid, Rifampicin • Vancomycin, Teicoplanin MRSA cover • • Daptomycin * No Staph aureus cover Gram-positive cover Antibiotic Gram Positive Gram Negative Atypicals MRSA Staph Strep Streptococci EF Anaerobes Resp Coliforms Pyo ESBL pneumo

Benzylpen / RR G G GGAA R RR R Pen icilli n V Flucloxacillin RG G G RRRR R RR R

Cefalexin RG G G RARR A RR R

Vancomycin & GG G G GGRR R RR R Teicoplanin

Linezolid GG G G GGAA R RR R

Daptomycin* GG R*G GGRR R RR R

Septrin® GG G G GRRA A AA

Clarithromycin RG G A RARG R RR G Clindamycin RG G G RGAR R RR A *Inactive in the lung 2. Narrow-spectrum Gram-negative agents • Ciprofloxacin • , Tobramicin, • Ceftazidime • Aztreonam • Colistin

All active against pseudomonas Gram-negative cover

Antibiotic Gram Positive Gram Negative Atypicals MRSA Staph Strep Streptococci EF Anaerobes Resp Coliforms Pyo ESBL pneumo

Nitrofurantoin* GG G G GRRR G RG R

Ciprofloxacin R A A A R R R G G G A G

Gentamicin / AG R R ARRG G GG R / Amikacin

Ceftazidime RA A A RARG G GR R

Aztreonam RR R R RRRG G GR R

Colistin RR R R RRRG G GA R

*Only active in urine 3. Anti-anaerobe agents

• • Clindamycin • Co-amoxiclav (“above the diaphragm” ) • Piperacillin-tazobactam • Ertapenem, imipenem, meropenem • Moxifloxacin Anaerobic cover

Antibiotic Gram Positive Gram Negative Atypicals MRSA Staph Strep Streptococci EF Anaerobes Resp Coliforms Pyo ESBL pneumo Metronidazole RR R R RGGR R RR R

Clindamycin RG G G RGAR R RR A

Co-amoxiclav RG G G GGAG G RR R

Pip-taz RG G G GGAG G GA R

Ertapenem RG G G AGGG G RG R Imipenem RG G G GGGG G GG R Meropenem R G G G A G G G G G G R

Tigecycline GG G G GGGG G RR G

Moxifloxacin AG G G GGGG G RA G 4. Anti-atypical agents

• – erythromycin, etc. • – , doxycycline etc. • Fluoroquinolones – ccpooac,ooac,eooaceciprofloxacin, ofloxacin, levofloxacin etc. Atypical cover

AibiiAntibiotic GPiiGram Positive GNiGram Negative Atyp ica ls MRSA Staph Strep Streptococci EF Anaerobes Resp Coliforms Pyo ESBL pneumo Tetracyclines DliDoxycycline G G G A R G A G A R A G GG G G RGAG A RA G

Tigecycline GG G G GGGG G RR G

Macrolides Erythromycin RA G A RARA R RR G Clarithromycin RG G A RARG R RR G AithAzithromyci n R G G A R A R G A R R G

Chlor- GG G G AGGG G RA G amphenicol

Ciprofloxacin RA A A RRRG G GA G Levofloxacin RG G G GAAG G GA G Moxifloxacin AG G G GGGG G RA G Broad spectrum cover Antibiotic Gram Positive Gram Negative Atypicals MRSA Staph Strep Streptococci EF Anaerobes Resp Coliforms Pyo ESBL pneumo Co-amoxiclav RG G G GGAG G RR R Cefuroxime RG G G RA RG G RR R

Ceftriaxone & RG G G RARG G RR R Cefotaxime

Timentin RG G G AGGG G GA R Pip-taz RG G G GGGG G GA R

Ertapenem R G G G A G G G G R G R Imipenem RG G G GGGG G GG R Meropenem RG G G AGGG G GG R

Chlor- GG G G AGGG G RA G amphenicol

Levofloxacin RG G G GAAG G GA G Moxifloxacin AG G G GGGG G RA G

Tigecycline GG G G GGGG G RR G Most important slide! Patient risk Low-risk patient High-risk patient \ •Mild-to-moderate infection •Severe or life-threatening infection PthPathogen •No prior antibiotics •No recent healthcare •Prior antibiotics group exposure •Healthcare exposure •NhitNo history o f mu lti-resitistant •His tory o f mu lti-resitistant pathogens pathogens Gram +ve Flucloxacillin or Vancomycin or Linezolid Clarithromycin or (MRSA cover) Doxycycline Gram –ve Trimethopp,rim, Co-amoxiclav, Gentamicin or Pip-taz Doxycycline, Ciprofloxacin Anaerobe Metronidazole or Co- Metronidazole or Pip-taz amoxiclav Atypical Doxycycline or IV Clarithromycin or Clarithromycin Ciprofloxacin Treatment failure? Is your patient circling the DRAInS

• D = Dose – Is th e d ose ad equat e? I s th e pati ent getti ng d oses? • R = Resistance – MRSA, Clostridium difficile, ESBL-ppgroducing Gram-negative – Virus, fungi, TB, parasite (malaria, opportunistic infection) • A = Allergy – Drug fever = unexplained fever despite improvement of other symptoms and CRP/WBC • In = Interaction – e.g. doxycycline absorption reduced by up to 90% by iron • S = SOURCE CONTROL – Antibiotic therapy alone may not cure infection – Incision & drainage, debridement, removal of line or prosthetic device Thank you for your attention

Happy to answer questions [email protected] Microbiota Antibiotics alter epithelial homeostasis in the gut and enhance host susceptibility to incoming pathogens

Willing BP Nature Reviews Microbiology 2011 Nature Reviews Microbiology: April 2011 The average child in a developed country has received 10-20 courses o f an tibio tics by the age o f 18. Blaser M, Nature, August 2011 Antibiotic “collateral” damage

• “Overuse of antibiot ics could be fuelling the dramatic increase in conditions such as obesity, type 1 diabetes, inflammatory bowel disease, allergies and asthma, which have more than doubled in many populations (see graph)?” Blaser M, Nature 2011 Prescribing Antibiotic use rising  Hospital prescribing trends: England

Ashiru Oredope D, JAC 2012 Hospital prescribing trends: Scotland

SAPG Report 2010 Unintended consequences?

Courtesy Prof Jonathan Cooke and IMS Health Inc Resistance threats Staphylococcus aureus bloodstream infections in England

Health Protection Agency Trends in bloodstream infections in England

Health Protection Agency The ebb and flow of resistance

Antibiotic resistance in E. coli from bacteraemia isolates for England & Wales (Health Protection Agency)

25

20 CEPH

ee CIP 15 resistanc 10 %

5

0 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011

Courtesy of Dr Alan Johnson, HPA ESBLs waxing and waning?

DH ARHAI ESBL report, February 2012 How to select out ESBL‐producers Carbapenem resistance in pseudomonas in Europe

www.rivm.nl/earss/ New Dehli Metallo‐betalactamase 1 (NDM‐1) carbapenemase: August 2010

Running out of options

Health Protection Report, June 2011 (n=333 in 2010) Carbapenem‐resistant coliforms resported to the HPA • Stool samples tested from 200 patients in Pakistan •Prevalence of NDM‐1 positive coliform carriage – 18/130 ()(14%) of outpatients – 19/70 (27%) of inpatients Clostridium difficile epidemic curve

Health Protection Report, February 2012 Clostridium difficile risk & antibiotics: new insights

2009/10 CDRN (national reference laboratory in Leeds) processed 5,720 faecal samples (C diff positive) from 172 healthcare facilities. 3,209 reported patient exposure to antibiotics. Therapeutics New contra‐indications, warnings and interactions for antimicrobials • Trimethoprim and hyperkalaemia –An 18‐year case‐control study found that 1.7% of patients concurrently treated with spironolactone and Septrin were admitted to hospital with hyperkalaemia within 2 weeks. – This rikisk is 12x hig her than for spiiltronolactone with amoxicillin. • Antoinou T et al, University of Toronto, BMJ 2011 • and cardiovascular death – During a 5‐day course, risk of cardiovascular death was 2.5‐fold higher with azithromycin vs amoxicillin – Risk of death from any cause was 2‐fold higher •Ray WA et al, N Engl J Med 17 May 2012 New contra‐indications, warnings and interactions for antimicrobials • SdiSodium fidtfusidate and sttitatins – Systemic fusidic acid should not be given with statins because of a risk of (potentially fatal) rhabdomyolysis – In patients for whom the use of systemic fidifusidic acid is essentilial, statin treatment should be temporarily discontinued throughout the duration of fusidic acid treatment – To ensure clearance of systemic fusidic acid, statin therapy may be reintroduced 7 days after the last dose of systemic fusidic acid •MHRA Drug Safety Update, September 2011

– Mechanism is unknown. Fusidic acid is not a known inhibitor of enzymes or transporters involved in statin metabolism. – Seven published cases with atorvastatin (3 fatal) and six with simvastatin. All had risk factors for myopathy or rhabdomyolysis. –An interaction between fusidic acid and the statins is not established. • Stockley’ s Drug Interactions, April 2012 New contra‐indications, warnings and interactions for antimicrobials • CbCarbapenems and sodium valtlproate –A clinically significant interaction between carbapenems and valproic acid/sodium valproate results in reduced valproate plasma concentrations with potential for inadequate seizure control –Given the large magnitude and rapid time course of this interaction, monitoring of sodium valproate levels or making dose adjustments are unlikely to manage this interaction –Concomitant use of carbapenems in patients taking valproic acid/sodium valproate is not recommended, and prescribers should consider alternative antibacterial therapy •MHRA Drug Safety Update, May 2010 –Plasma levels of valproate fall by 66% (34‐92%) within 24 hours of starting meropenem, associated with worsening seizures or EEG in 55% – Mechanism possibly altered protein binding and increased glucuronidation with enhanced renal excretion •Stockley ’s Drug Interactions, April 2012 Worrying Warnings

• Tigecyc line (Tygac il▼): idincreased mortality in clin ica l trials –use only when other antibiotics are unsuitable (Drug Safety Update 04Apr11) •Daptomycin: risk of eosinophilic pneumonia (DSU 10Feb11) • Moxifloxacin (Avelox ▼) : Because of evidence of an increased risk of life‐threatening liver reactions and other serious risks (such as QT interval prolongation), oral moxifloxacin should be used only when other antibacterials are inappropriate or ineffective (DSU Jan11) New antimicrobials 1: fidaxomicin

• Narrow‐spectrum (Gram‐posiiitive ), first‐in‐class, macrocyclic antibiotic that has minimal absorption from the GI tract • Activity against Clostridium difficile but little effect on faecal microbiota • Bactericidal, inhibits RNA polymerase • 1,000 patients evaluable in two Phase 3 studies. Cure rate after 10 days was 88% in the FDX group versus 86% in the oral vancomycin group. • Clinical recurrence rates were 13% after FDX vs 24.5% after vancomycin per protocol (NNT = 8.7). At £1,350 per treatment course, this puts the cost of preventing one recurrence at £11,750 (exc VAT). New antimicrobials 2: ceftaroline

• New parenteral cephhlalospor in wiihth actiiivity against mulilti‐ drug‐resistant Gram‐positives including MRSA, VRE and penicillin‐resistant Streptococcus pneumoniae • 600mg IV infusion 12‐hourly •Not active against Pseudomonas aeruginosa or other non‐ fermenter Gram‐negatives • Ceftaroline non‐inferior to vancomycin for skin and skin structure infections (91.6% vs 92.7% cure). • Ceftaroline non‐inferior to ceftriaxone for community‐ acquired pneumonia (86.6% vs 78.2% cure). • Two cases of C. difficile in Phase 3 ceftaroline arms. •May be less expensive than linezolid or dapyptomycin. Renaissance of older antimicrobials 1: fosfomycin •Didiscovered in the 1970s • Inhibits a transferase enzyme that catalyses the first step of bacterial cell wall synthesis • Retains activity against many resistant Gram‐ negative bacteria including ESBL‐producers • Licensed in the UK but no UK stock available so imported •Given as 3g oral sachet single dose or q48h for lower UTI Renaissance of older antimicrobials 2: colistin

•We underdose colistin • Loading dose of 10MU required for 70kg patient • Followed after 24h by 5MU 12‐hourly (CrCl 60mL/min) Pharmacokinetics / Pharmacodynamics / (Toxicodynamics) PK/PD parameters affecting antibiotic efficacy in vivo Concentration Cmax:MIC

AUC:MIC

MIC TTMIC>MIC PAE 0 Time (()hours) PK/PD relationships for different antibiotics

Roberts J Crit Care Med 2009 PK/PD dosing of meropenem

MPKfdifftIVbldiiMeropenem PK for different IV bolus dosing regimens

60

50

40 (mg/L) 1 gram 8-hourly 30 500mg 6-hourly Breakpoint (4mg/L) m levels levels m

uu 20 Ser 10

0 012345678910111213 Time (hours) 72 Equivalent response of PK/PD dosing in neutropenic patients

73

Arnold H, Pharmacotherapy 2009; 29(8): 914-923 Thank you for your attention

Happy to answer questions [email protected]